# Off-patent compounds and missing trials

Rating: Promising — Some human trials, or consistent animal work with a clear mechanism
Type: Method
Updated: 2026-11-01
Canonical: https://heretic.bio/articles/off-patent-compounds-and-missing-trials.html

> Companies fund large trials when a win can be protected and sold. For generics and unpatentable compounds the expected return is low or absent, and most repurposing research is left to academics (Verbaanderd 2020). That explains why metformin for ageing, DMSO and low-dose naltrexone lack decisive trials. It does not mean they work. Public trials of cheap drugs have found big wins, such as dexamethasone in Covid-19, and clear failures, such as LDN in Crohn's disease.

> Large randomised trials are expensive and slow. Companies pay for that when a win can be sold under patent or regulatory exclusivity. A cheap generic, a solvent or a molecule anyone can make offers no such return, so the decisive trial often never happens. That is a real gap, and this page documents it. It is also not evidence that the compound works: when public funders do run the trials, cheap compounds sometimes win big and sometimes fail.

## Why the trials are missing

  * **The return is low or absent.** A 2020 policy review of repurposing cancer drugs found that getting a new indication approved carries a high administrative burden and significant costs, while the return on investment for industry is expected to be low or absent for medicines out of patent and regulatory protection. Most repurposing research is done by independent or academic researchers who lack the resources to take a drug through regulators (Verbaanderd 2020, [PMID 32076405](https://pubmed.ncbi.nlm.nih.gov/32076405/)).
  * **The science is not the bottleneck.** A 2019 review in _Nature Reviews Drug Discovery_ describes old drugs as de-risked compounds with potentially lower development costs and shorter timelines, but lists major technological and regulatory challenges for repurposing (Pushpakom 2019, [PMID 30310233](https://pubmed.ncbi.nlm.nih.gov/30310233/)).
  * **Some compounds cannot be owned at all.** A 2021 review called DMSO "nonpatentable" and "underexplored and ignored by pharmaceutical developers" (Hoang 2021, [PMID 34314611](https://pubmed.ncbi.nlm.nih.gov/34314611/)). The authors are advocates of the compound, so read the claim as a description of the incentive, not proof of efficacy.



## Cases on this site

  * **Metformin for ageing.** The TAME trial was proposed in 2016 to test metformin against a composite of age-related diseases (Barzilai 2016, [PMID 27304507](https://pubmed.ncbi.nlm.nih.gov/27304507/)). Ten years later no results have been published. See [metformin and rapamycin](metformin-and-rapamycin.html).
  * **Pyridoxamine.** A form of vitamin B6 that a drug developer had pulled from US supplement shelves. The drug programme then stopped for lack of money, not because a trial failed. See [the drug-exclusion rule](drug-exclusion-rule-pyridoxamine-nmn-nac.html).
  * **DMSO, low-dose naltrexone and low-dose lithium.** All are cheap and off-patent, with small trials and large claims. See [DMSO](dmso-therapy.html), [low-dose naltrexone](low-dose-naltrexone-ldn-evidence-taxonomy.html) and [low-dose lithium](low-dose-lithium-and-alzheimers.html).



## When public money runs the trial

The gap is not fixed. Public and charity funders can run trials of cheap drugs, and the results go both ways.

  * **Dexamethasone.** The UK RECOVERY trial, funded by the Medical Research Council and the National Institute for Health Research, randomised 6,425 hospitalised Covid-19 patients. A decades-old generic steroid cut 28-day deaths (22.9% versus 25.7%; rate ratio 0.83) (Horby 2021, [PMID 32678530](https://pubmed.ncbi.nlm.nih.gov/32678530/)).
  * **Colchicine.** COLCOT, funded by the Government of Quebec and others, found fewer cardiovascular events after a heart attack (5.5% versus 7.1%) (Tardif 2019, [PMID 31733140](https://pubmed.ncbi.nlm.nih.gov/31733140/)). LoDoCo2, supported by Australian and Dutch public and charitable funders plus a consortium of Dutch generic makers (Teva, Disphar and Tiofarma), found fewer events in chronic coronary disease (6.8% versus 9.6%) (Nidorf 2020, [PMID 32865380](https://pubmed.ncbi.nlm.nih.gov/32865380/)). Once that evidence existed, a branded low-dose colchicine tablet won FDA approval in 2023, which shows the other route: a company can still make money on an old molecule after someone else has paid for the proof. Then CLEAR SYNERGY, the largest trial after a heart attack, found no benefit ([PMID 39555823](https://pubmed.ncbi.nlm.nih.gov/39555823/)). See [low-dose colchicine](low-dose-colchicine-cardiovascular-inflammation.html).
  * **Low-dose naltrexone.** A Dutch multicentre placebo-controlled trial in active Crohn's disease was stopped early for futility: endoscopic remission was 5.6% with LDN versus 18.8% with placebo, with less fatigue as the only signal (van de Pol 2026, [PMID 42701992](https://pubmed.ncbi.nlm.nih.gov/42701992/)). A missing sponsor explains why LDN trials are small; it does not explain away a null one.



## How to read a cheap compound's evidence

  * "No big trial" means unknown, not proven and not disproven.
  * Check the registries for publicly funded trials before assuming nobody has tested it.
  * Treat advocates' reviews the way you would treat a sponsor's review: the incentive is reputation or a clinic, not a patent. See [industry funding and trial results](industry-funding-and-trial-results.html).
  * When a well-run public trial is null, weigh it fully. Cheapness does not make a compound more likely to work.



This page explains how evidence gets made; it is not medical advice.

## Who paid, and how it got here

### Who paid for the key studies

- RECOVERY trial, dexamethasone in Covid-19, n=6,425: A cheap generic steroid cut 28-day deaths. Funding and interests: UK Medical Research Council and NIHR (public funding). ([Paper's funding statement](https://pubmed.ncbi.nlm.nih.gov/32678530/))
- COLCOT, colchicine after heart attack, n=4,745: Fewer cardiovascular events with colchicine. Funding and interests: Government of Quebec and others (public funding). ([Paper's funding statement](https://pubmed.ncbi.nlm.nih.gov/31733140/))
- LoDoCo2, colchicine in chronic coronary disease, n=5,522: Fewer cardiovascular events with colchicine. Funding and interests: Australian and Dutch public/charitable support, plus Teva, Disphar and Tiofarma. ([Paper's funding statement](https://pmc.ncbi.nlm.nih.gov/articles/PMC12184580/))

Checked 2026-11-01.

## Sources

1. Verbaanderd C, Rooman I, Meheus L, Huys I. On-label or off-label? Overcoming regulatory and financial barriers to bring repurposed medicines to cancer patients. Front Pharmacol. 2020;10:1664. PMID 32076405 (PubMed 32076405)
2. Pushpakom S, Iorio F, Eyers PA et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov. 2019;18(1):41-58. PMID 30310233 (PubMed 30310233)
3. Hoang C, Nguyen AK, Nguyen TQ et al. Application of dimethyl sulfoxide as a therapeutic agent and drug vehicle for eye diseases. J Ocul Pharmacol Ther. 2021;37(8):441-451. PMID 34314611 (PubMed 34314611)
4. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060-1065. PMID 27304507 (PubMed 27304507)
5. RECOVERY Collaborative Group; Horby P et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704. PMID 32678530 (PubMed 32678530)
6. Tardif JC et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019. PMID 31733140 (PubMed 31733140)
7. Nidorf SM et al. Colchicine in patients with chronic coronary disease. N Engl J Med. 2020. PMID 32865380 (PubMed 32865380)
8. Jolly SS et al. Colchicine in acute myocardial infarction. N Engl J Med. 2025. PMID 39555823 (PubMed 39555823)
9. van de Pol N, Paulides E, Wolfhagen FHJ et al. Low-dose naltrexone in Crohn's disease: a prematurely terminated randomized trial. Dig Dis Sci. 2026. PMID 42701992 (PubMed 42701992)